Autophagy regulation of RSV-induced pulmonary disease

摘要 肺中抗病毒免疫应答的调节依赖于有效和有效地调节肺内抗病毒免疫应答的能力。 适当地识别致病信号并促进适当的和非致病的反应。 呼吸道合胞病毒（RSV）是一种特别致病的病毒，可在所有年龄段引起发病， 特别是在婴儿和那些有潜在肺部疾病的人中。我们最近公布的数据从我们现在的 资金周期表明，一个关键的先天免疫途径，是调节致病性 免疫反应是自噬。这个无所不在的过程为所有细胞提供了不仅保存 资源，但运输病原体成分适当的免疫识别分子。这尤其 这一过程似乎是树突状细胞活化、细胞因子产生和随后的T细胞增殖的中心。 activation.在这次更新中，我们将继续研究改变自噬的后果，包括 ER应激和炎性小体激活的调节，导致先天性细胞因子谱的明显转变。 我们将更密切地和机械地继续探索自噬诱导剂Sirtuin 1的作用， NAD+脱乙酰酶，其不仅对自噬谱的调节作用，而且对直接和间接自噬的调节作用， 它对ER应激和炎性小体活化具有间接作用。使用Sirt 1-/-并沿着Sirt 1进行抑制 我们将探讨Sirt 1的缺失沿着自噬的减少， 在体外和体内改变抗RSV应答。增加的ER应激诱导的细胞因子模式的转变， 自噬和Sirt 1的缺乏可导致由于增强的致病性而改变的致病性表型， T细胞反应，尤其是IL-17。因此，这些研究将探索几种新的和局部的途径， 不仅进一步明确了促进肺粘膜免疫应答的机制， 了解RSV感染和免疫。

Abstract The regulation of anti-viral immune responses in the lung is dependent upon the ability to efficiently and appropriately recognize pathogenic signals and promote the proper and non-pathogenic response. Respiratory syncytial virus (RSV) is an especially pathogenic virus that can induce morbidity at all ages, especially in infants and those with underlying lung conditions. Our recent data published from our present funding cycle indicated that a critical innate immune pathway that is functional for regulating pathogenic immune response is autophagy. This omnipresent process provides all cells the ability to not only preserve resources but transport pathogen components to the proper immune recognition molecules. In particular, this process appears to be central for dendritic cell activation, cytokine production, and subsequent T cell activation. In this renewal, we will continue to examine the consequences of altering autophagy, including the regulation of ER stress and inflammasome activation, that leads to a distinct shift in innate cytokine profiles. We will more closely and mechanistically continue to explore the role of an autophagy inducer, Sirtuin 1, a NAD+ deactylase, and its effect on the regulation of not only the autophagy profiles, but also the direct and indirect effect it has on ER stress and inflammasome activation. Using Sirt1 -/- and inhibition along with Sirt1 overexpression and activation we will explore how the absence of Sirt1 along with the reduction of autophagy alters anti-RSV responses in vitro and in vivo. The shift in cytokine patterns induced by increased ER stress in the absence of autophagy and Sirt1 can lead to an altered pathogenic phenotype due to enhanced pathogenic T cell responses, especially IL-17. Thus, these studies will explore several novel and topical pathways that will not only further define the mechanisms that promote pulmonary mucosal immune responses, but expand our understanding of RSV infection and immunity.